Title: Butyrate Protects Mice from Clostridium difficile-Induced Colitis through an HIF-1-Dependent Mechanism
Author: Mendonça, Monique Culturato Padilha; Radaic, Allan; Garcia-fossa, Fernanda; Da Cruz-höfling, Maria Alice; Vinolo, Marco Aurélio Ramirez; De Jesus, Marcelo Bispo
Is part of: Drug Delivery and Translational Research, v. 9, p. 1 - 9
Citation: Mendonça, Monique Culturato Padilha; Radaic, Allan; Garcia-fossa, Fernanda; Da Cruz-höfling, Maria Alice; Vinolo, Marco Aurélio Ramirez; De Jesus, Marcelo Bispo; Butyrate Protects Mice from Clostridium difficile-Induced Colitis through an HIF-1-Dependent Mechanism. Drug Delivery and Translational Research, v.9, p. 1-9, 2019
Abstract: Antibiotic-induced dysbiosis is a key factor predisposing intestinal infection by Clostridium difficile. Here, we show that interventions that restore butyrate intestinal levels mitigate clinical and pathological features of C. difficile-induced colitis. Butyrate has no effect on C. difficile colonization or toxin production. However, it attenuates intestinal inflammation and improves intestinal barrier function in infected mice, as shown by reduced intestinal epithelial permeability and bacterial translocation, effects associated with the increased expression of components of intestinal epithelial cell tight junctions. Activation of the transcription factor HIF-1 in intestinal epithelial cells exerts a protective effect in C. difficile-induced colitis, and it is required for butyrate effects. We conclude that butyrate protects intestinal epithelial cells from damage caused by C. difficile toxins via the stabilization of HIF-1, mitigating local inflammatory response and systemic consequences of the infection.
Funding: This study was supported by Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP; grants 2012/10653-9, 2013/06810-4, 2014/03002-7, 2015/06134-4, 2017/16280-3, and 2018/01753-6), Funcamp, National Council for Scientific and Technological Development (CNPq), Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior - Brasil (CAPES) - Finance Code 001, a Newton Advanced Fellowship by the Royal Society (between M.A.R.V. and P.V.-W.). J.L.F., L.P.P., B.K.S., R.O.C., Y.T.M., and T.C. are recipients of fellowships from FAPESP (2017/06577-9, 2018/02208-1, 2017/25679-7, 2016/23142-3, 2017/01451-7, and 2017/26366-2). A.M.T. was supported by a fellowship from FAPESP (2015/01507-7). We thank Juri Kazakevych for help with the RNA sequencing analyses and Maria Teresa Pedrosa Silva Clerici for the formulation of the diets.